Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups

ABSTRACT

Process for the preparation of a derivative or analog of baccatin III or 10-desacetyl baccatin III having a C2 substituent other than benzoate and/or a C4 substituent other than acetate in which the C2 benzoate substituent and/or the C4 acetate substituent of a derivative of baccatin III or 10-desacetyl baccatin III is/are selectively reduced to the corresponding hydroxy group(s) and converted to R 7  COO- and/or R 8  COO-, respectively, wherein R 7  and R 8  are independently H, C 1  -C 6  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, moncyclic aryl, or monocyclic heteroaryl.

This invention was made with Government support under NIH Grant #CA42031 and Grant #CA 55131 awarded by the National Institute of Health.The Government has certain rights in the Invention.

BACKGROUND OF THE INVENTION

The present invention relates to a process for the preparation ofbaccatin III and 10-desacetyl baccatin III analogs having new C2 and/orC4 functional groups.

Taxol is a natural product extracted from the bark of yew trees. It hasbeen shown to have excellent antitumor activity in in vivo animalmodels, and recent studies have elucidated its unique mode of action,which involves abnormal polymerization of tubulin and disruption ofmitosis. It is currently undergoing clinical trials against ovarian,breast and other types of cancer in the United States and France andpreliminary results have confirmed it as a most promisingchemotherapeutic agent. The structure of taxol and the numbering systemconventionally used is shown below; this numbering system is alsoapplicable to compounds used in the process of the present invention.##STR1##

In Colin U.S. Pat. No. 4,814,470, it was reported that a taxolderivative, commonly referred to as taxotere, has an activitysignificantly greater than taxol. Taxotere has the following structure:##STR2##

In copending application, U.S. application Ser. No. 07/949,449, filedSep. 22, 1992, it is reported that 10-desacetoxytaxol and relatedcompounds also exhibit anti-tumor activity. Compounds disclosed in thiscopending application include: ##STR3##

Taxol, taxotere and other biologically active tetracyclic taxanes may beprepared semisynthetically from baccatin III and 10-desacetyl baccatinIII as set forth in U.S. Pat. Nos. 4,924,011 and 4,924,012 or by thereaction of a β-lactam and a suitably protected baccatin III or10-desacetyl baccatin III ("10-DAB") derivative as set forth in U.S.Pat. No. 5,175,315 or copending U.S. Patent application Ser. No.07/949,107 (which is incorporated herein by reference). Baccatin III 1and 10-DAB 2 can be separated from mixtures extracted from naturalsources such as the needles, stems, bark or heartwood of numerous Taxusspecies and have the following structures. ##STR4##

The tetracyclic core of taxol and taxotere bear six singly bonded oxygensubstituents. Two of these (three in the case of taxotere) are presentas hydroxyl groups, and the others are esters of three differentcarboxylic acids. Selective manipulation of these groups presents aformidable problem which must be overcome before a series of taxolanalogs can be prepared by a rational synthetic sequence. Hydrolytic andsolvolytic methods have previously encountered complications. Forexample, it has been reported by that hydrolysis of taxol under mildlybasic conditions yields a complex mixture of products. Miller et al., J.Org. Chem. 1981, 46, 1469. Recently it has been found that solvolysis ofbaccatin (III) derivatives leads to rearrangement of the tetracycliccore, Farina, et al., Tetrahedron Lett. 1992, 33, 3979.

SUMMARY OF THE INVENTION

Among the objects of the present invention, therefore, is the provisionof a process for selectively attaching different functional groups tothe C2 and/or C4 oxygens of baccatin III and analogs or derivativesthereof; the provision of such a process which is relativelystraightforward; the provision of such a process in which the C2benzoate substituent of baccatin III and analogs or derivatives thereofmay be selectively reduced and the provision of such a process in whichthe C4 acetate substituent may be selectively reduced.

Briefly, therefore, the present invention is directed to a process forthe preparation of analogs or derivatives of baccatin III or10-desacetyl baccatin III in which the C2 benzoate substituent and/orthe C4 acetate substituent of baccatin III or 10-desacetoxy baccatin IIIare selectively reduced to the corresponding hydroxy group(s). Thereduced baccatin III or 10-desacetyl baccatin III is thereafterconverted to a baccatin III or 10-desacetyl derivative having theformula ##STR5## wherein R₁ is H, --OH, protected hydroxy, or --OCOR₆,

R₂ is H, a hydroxy protecting group, or ##STR6## R₃ is H or R₇ CO--, R₄is H or R₈ CO--,

R₅ is H, --OH or protected hydroxy,

R₆, R₇, and R₈ are independently H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, monocyclic aryl, or monocyclic heteroaryl.

R₉ is --OR₁₄, --SR₁₅, or --NR₁₆ R₁₇ ;

R₁₀ is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

R₁₁ and R₁₂ are independently hydrogen, alkyl, or alkenyl, alkynyl,aryl, acyl or heteroaryl, provided R₁₁ and R₁₂ are not both acyl;

R₁₃ is --COR₁₈, --COOR₁₈, --COSR₁₈, --CONR₁₂ R₁₈, or --SO₂ R₁₉,

R₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxyprotecting group,

R₁₅ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydrylprotecting group,

R₁₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R₁₁ is anamino protecting group;

R₁₈ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, and

R₁₉ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR₁₅, or --NR₁₂ R₁₆.

The present invention is additionally directed to a derivative ofbaccatin III or 10-desacetyl baccatin III having the formula ##STR7##wherein R₁, R₂, R₄, and R₅ are as previously defined.

Other objects and features of this invention will be in part apparentand in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

As used herein "Ar" means aryl; "Ph" means phenyl; "Ac" means acetyl;"R" means alkyl unless otherwise defined; "tBu" means t-butyl; "TES"means triethylsilyl; "TMS" means trimethylsilyl; "DMAP" meansp-dimethylamino pyridine; "DMF" means dimethylformamide; "LDA" meanslithium diisopropylamide; "LAH" means lithium aluminum hydride; "Red-Al"means sodium bis(2-methoxyethoxy) aluminum hydride; "10-DAB" means10-desacetyl baccatin III; protected hydroxy means --OR wherein R is ahydroxy protecting group; sulfhydryl protecting group includes, but isnot limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl,thioesters, or thiocarbonates; "amine protecting group" includes, but isnot limited to, carbamates, for example, 2,2,2-trichloroethylcarbamateor tertbutylcarbamate; and "hydroxy protecting group" includes, but isnot limited to, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl,p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl,ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilylethers such as trimethylsilyl ether, triethylsilyl ether,dimethylarylsilyl ether, triisopropylsilyl ether andt-butyldimethylsilyl ether; esters such as benzoyl, acetyl,phenylacetyl, formyl, mono-, di-, and trihaloacetyl such aschloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro- acetyl; andcarbonates including but not limited to alkyl carbonates having from oneto six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to sixcarbon atoms and substituted with one or more halogen atoms such as2,2,2-trichloroethoxymethyl and 2,2,2-trichloro-ethyl; alkenylcarbonates having from two to six carbon atoms such as vinyl and allyl;cycloalkyl carbonates have from three to six carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl orbenzyl carbonates optionally substituted on the ring with one or moreC₁₋₆ alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protectinggroups may be found in "Protective Groups in Organic Synthesis" by T. W.Greene, John Wiley and Sons, 1981.

The alkyl groups described herein, either alone or with the varioussubstituents defined hereinabove are preferably lower alkyl containingfrom one to six carbon atoms in the principal chain and up to 15 carbonatoms. They may be straight or branched chain and include methyl, ethyl,propyl, isopropyl, buryl, isobutyl, tert-butyl, aryl, hexyl, and thelike.

The alkenyl groups described herein, either alone or with the varioussubstituents defined hereinabove are preferably lower alkenyl containingfrom two to six carbon atoms in the principal chain and up to 15 carbonatoms, They may be straight or branched chain and include ethenyl,propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like.

The alkynyl groups described herein, either alone or with the varioussubstituents defined hereinabove are preferably lower alkynyl containingfrom two to six carbon atoms in the principal chain and up to 15 carbonatoms. They may be straight or branched chain and include ethynyl,propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.

The aryl moieties described herein, either alone or with varioussubstituents, contain from 6 to 15 carbon atoms and include phenyl.Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl,alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the morepreferred aryl.

The heteroaryl moieties described herein, either alone or with varioussubstituents, contain from 5 to 15 atoms and include, furyl, thienyl,pyridyl and the like. Substituents include alkanoxy, protected hydroxy,halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc.

Surprisingly, it has been discovered that the C2 ester of a suitablyprotected derivative of baccatin III or 10-DAB may be selectivelyreduced to form a 1,2 diol having the formula ##STR8## which may beconverted to a 1,2 carbonate intermediate having the formula ##STR9##wherein R₁, R₂, R₄, and R₅ are as previously defined, This carbonatepermits the selective formation of a variety of C2 esters throughreaction with alkyl, alkenyl, alkynyl or aryl lithium reagents orGrignard reagents.

Any reducing agent which selectively reduces the C2 and/or C4 esters tothe corresponding alcohol may be used. The reducing agent is preferablyan aluminate and, most preferably, the reducing agent is lithiumaluminum hydride ("LAH") or sodium bis(2-methoxyethoxy) aluminum hydride("Red-Al").

After the C2 and/or C4 esters are reduced to the correspondingalcohol(s), standard acylating agents such as anhydrides and acidchlorides in combination with an amine such as pyridine, triethylamine,DMAP, or diisopropyl ethyl amine can be used to form new esters at C2and/or C4. Alternatively, the C2 and/or C4 alcohols may be converted tonew C2 and/or C4 esters through formation of the corresponding alkoxideby treatment of the alcohol with a suitable base such as LDA followed byan acylating agent such as an acid chloride.

As will be discussed in greater detail below, baccatin III and 10-DABderivatives having new C2 and/or C4 esters can be produced by severalreaction schemes. To simplify the description, 10-DAB is used as thestarting material in Reaction Schemes 1-6. It should be understood,however, that baccatin III derivatives or analogs may be produced usingthe same reactions (except for the protection of the C10 hydroxy groupwith TES) by simply replacing 10-DAB with baccatin III as the startingmaterial.

10-DAB derivatives having a C2 hydroxy substituent or alternative C2ester can be prepared as set forth in Reaction Scheme 1. ##STR10##

In Reaction Scheme 1, the C7 hydroxyl group of 10-deacetyl baccatin(TIT) was selectively protected as its triethylsilyl (TES) ether asdescribed by Green, et al,, JACS 110, 5917 (1988). The C10 hydroxylgroup was then protected as the TES ether through the use ofn-butyllithium and triethylsilyl chloride, The C13 hydroxyl group wassubsequently protected as the trimethylsilyl (TMS) ether, which could beselectively removed at a later stage. The fully protected13-O-tdmethylsilyl-7,10-bis-O-triethylsilyl-10-deacetyl baccatin (III) 3underwent selective reduction with Red-Al to give the 2 hydroxyderivative 4. Deprotonation of 4 with either n-butylithium or a bulkyamide base such as LDA was followed by the addition of an appropriateacid chloride to provide the C2 ester derivative 5. The C13 TMS groupmay then be removed using HF.

Alternatively, as shown in Reaction Scheme 2, 1,2 diol 4 can be readilyconverted to the 1,2 carbonate 6 which can be transformed to the C2formate 5 (R₃ =HCO) by treatment with Red-Al under mild conditions. Inaddition, carbonate 6 reacts selectively with nucleophilic agents (e.g.,Grignard reagents or alkyllithium reagents) to provide the C2 esterderivative 5 (R₃ =R₇ CO). Again, the C13 TMS group may then be removedusing HF. ##STR11##

10-DAB analogs having different substituents only at C4, or at both C2and C4 can be prepared as set forth in Reaction Schemes 3-6.

In Reaction Scheme 3, protected 10-DAB 3 is converted to the triol 7with lithium aluminum hydride. Triol 7 is then converted to thecorresponding C4 ester using Cl₂ CO in pyridine followed by anucleophilic agent (e.g., Grignard reagents or alkyllithium reagents).##STR12##

Alternatively, deprotonation of triol 7 with LDA followed byintroduction of an acid chloride selectively gives the C4 ester. Forexample, when acetyl chloride was used, triol 7 was converted to 1,2diol 4 as set forth in Reaction Scheme 4. ##STR13##

Triol 7 can also readily be converted to the 1,2 carbonate 8.Acetylation of carbonate 8 under vigorous standard conditions providescarbonate 6 as described in Reaction Scheme 5; addition of alkyllithiumsor Grignard reagents to carbonate 6 provides the C2 ester having a freehydroxyl group at C4 as set forth in Reaction Scheme 2. As set forth inReaction Scheme 6, other C4 substituents can be provided by reactingcarbonate 8 with an acid chloride and a tertiary amine to yieldcarbonate 10 which is then reacted with alkyllithiums or Grignardreagents to provide 10-DAB derivatives having new substituents at C2 asset forth in Reaction Scheme 6. ##STR14##

Alternatively, baccatin III may be used as a starting material andreacted as shown in Reaction Scheme 7. After being protected at C7 andC13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 12.Tetraol 12 is converted to carbonate 13 using Cl₂ CO and pyridine, andcarbonate 13 is acylated at C10 with an acid chloride and pyridine toproduce carbonate 14 (as shown) or with acetic anhydride and pyridine(not shown). Acetylation of carbonate 14 under vigorous standardconditions provides carbonate 15 which is then reacted with alkyllithiums to provide the baccatin III derivatives having new substituentsat C2 and C10. ##STR15##

10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives of10-DAB having alternative C2 and C4 substituents may be produced usingthe same reactions (except for the protection of the C10 hydroxy groupwith TES) by simply replacing 10-DAB with 10-desacetoxy baccatin III asthe starting material in Reaction Schemes 1-6. Baccatin III and 10-DABmay be selectively and nearly quantitatively converted to thecorresponding 10-desacetoxy or 10-desoxytaxane when they are reactedwith samarium diiodide. Alternatively, the 10-DAB derivatives havingalternative C2 and C4 substituents may themselves be reacted withsamarium diiodide to yield the corresponding 10-deacetoxy compound.

Synthesis of tetracyclic taxaries having a C13 side-chain and differentsubstituents at C2 and/or C4 can readily be prepared from baccatin IIIand 10-DAB derivatives having different substituents at C2 and/or C4using presently known methods. For instance, a suitable side chain maybe attached to a baccatin III or 10-DAB derivative as set forth in U.S.Pat. Nos. 4,924,011 and 4,924,012 or by the reaction of a β-lactam and asuitably protected baccatin III or 10-desacetyl baccatin III derivativeas set forth in U.S. Pat. No. 5,175,315 or copending U.S. Patentapplication Ser. No. 07/949,107.

The following examples are provided to more fully filustrate theinvention.

EXAMPLE 1 PROTECTION OF 10-DEACETYL BACCATIN (III) AT C7, C10 AND C13##STR16##

7-O-Triethylsilyl-10-deacetyl baccatin (III). To a solution of10-deacetyl baccatin (III ) (1.5 g, 2.8 mmol) in 100 mL of pyridine wasadded 4.7 mL (10 eq) of triethylsilyl chloride (TESCl) and the mixturewas stirred for 24 h at 25° C. The reaction mixture was diluted withEtOAc (800 mL) and washed with H₂ O (2×200 mL) and 10% aqueous CuSO₄until all pyridine was removed. The organic layer was washed with brine(50.0 mL), dried over anhydrous Na₂ SO₄, filtered, and concentrated togive crude product (1.92 g). Plug filtration from 20% EtOAc in hexane to50% EtOAc in hexane gave 7-O-triethylsilyl-10-deacetyl baccatin (III)(1.78 g, 97.7% ). m.p. 257°-258° C. [α]²⁵ _(Na) -23.8° (c 0.5 CHCl₃) ¹ HNMR (CDCl₃, 300 MHz) δ8.10 (d, J=7.1 Hz, 2H, benzoate ortho), 7.63-7.45(m, 3H, aromatic), 5.60 (d, J=7.2 Hz, 1H, H2), 5.17 (d, J=1.7 Hz, 1H,H10), 4.95 (dd, J=1.7, 9.9 Hz, 1H, H5), 4.88 (m, 1H, H13), 4.41 (dd,J=6.6, 10.4 Hz, 1H, H7), 4.31 (d, J=8.2 Hz, 1H, H20α), 4.16 (d, J=8.2Hz, 1H, H20β), 3.95 (d, J =7.1 Hz, 1H, H3), 2.49 (m, 1H, H6α), 2.28 (s,3H, 4Ac), 2.10-2.09 (m, 2H, H14α, H14β), 2.08 (s, 3H, Me18), 1.90 (m,1H, H6β), 1.73 (s, 3H, Me19), 1.19 (s, 3H, Me17), 1.08 (s, 3H, Me16),1.02-0.93 (m, 9H, SiCH₂ CH₃), 0.59-0.51 (m, 6H, SiCH₂ CH₃). ##STR17##

7,10-Bis-O-triethylsilyl-10-deacetyl baccatin (III). To a solution of7-O-triethylsilyl-10-deacetyl baccatin (III) (1.0 g, 1.55 mmol) in 20 mLof THF at -78° C. under N₂ was added 1.04 mL of a 1.64 M solution ofn-butyllithium (1.1 equiv) in hexane. The mixture was stirred for 30rain at -78° C. and 0.31 mL (1.2 equiv) of TESCl was added dropwise. Themixture was stirred for 1h at -78° C. and 10 mL of saturated aqueousNaHCO₃ was added. The solution was diluted with EtOAc (80.0 mL). Theorganic phase was washed with brine (15.0 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a crudesolid (1.45 g) . Flash chromatography from 25% EtOAc in hexane to 50%EtOAc in hexane gave 7,10-bis-O-triethylsilyl-10-deacetyl baccatin (III)(0.63 g, 53.6 %) and recovered 7-O-triethylsilyl-10-deacetyl baccatin(III) (0.35 g, 35.0%). m.p. 184°-186° C. [α]²⁵ _(Na) -46 0° (c 0.5CHCl₃) ¹ H NMR (CDCl₃, 300 MHz) δ8.10 (d, J=6.6 Hz, 2H, benzoate ortho),7.6-7.4 (m, 3H, aromatic), 5.61 (d, J =7.1 Hz, 1H, H2), 5.21 (s, 1H,H10), 4.93 (dd, J=1.7, 9.3 Hz, 1H, H5), 4.82 (m, 1H, H13), 4.42 (dd,J=6.6, 10.4 Hz, 1H, H7), 4.27 (d, J=8.2 Hz, 1H, H20α), 4.14 (d, J=8.2Hz, 1H, H20β), 3.91 (d, J=6.6 Hz, 1H, H3) 2.53 (m, 1H, H6α), 2.27 (s,3H, 4Ac), 2.25 (m, 2H, H14α, H14β), 2.03 (s, 3H, Me18 ), 1.85 (m, 1H,H6β), 1.64 (s, 3H, Me19), 1.18 (s, 3H, Me17), 104 (s, 3H, Me16),1.02-0.85 (m, 18H, SiCH₂ CH₃), 0.69-0.58 (m, 12H, SiCH₂ CH₃). ##STR18##

13-O-Triethylsilyl-7,10-bis-O-triethylsilyl-10-deacetyl baccatin (III).To a solution of 0.5 g (0.66 mmol) of7,10-bis-O-triethylsilyl-10-deacetyl baccatin (III ), 90 mg (2 eq) ofimidazole, 40 mg (0.5 eq) of p-dimethylaminopyridine (DMAP) in 15 mL ofCH₂ Cl₂ at 0° C. was added 0.17 mL (2 eq) of trimethylsilyl chloride(TMSCl). The solution was stirred at 0° C. for 30 rain and 1.0 mL ofmethanol was added. The mixture was diluted with H₂ O (10.0 mL) andEtOAc (50.0 mL) and the organic layer was separated, washed with brine(10.0 mL), dried over anhydrous Na₂ SO₄, filtered and concentrated underreduced pressure to afford a crude solid (0.58 g) . Plug filtration with10% EtOAc in hexane gave13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-10-deacetyl baccatin (III)(0.53 g, 96.5%). m.p. 213°-215° C. [α] ²⁵ _(Na) -43.0° (c 0.5, CHCl₃), ¹H NMR (CDCl3, 300 MHz), δ8.10 (d, J=7.1 Hz, 2H, benzoate ortho), 7.6-7.4(m, 3H, aromatic), 5.62 (d, J 32 7.1 Hz, 1H, H2), 5.19 (s, 1H, H10),4.94, (dd, J=1.8, 8.8 Hz, 1H, H5), 4.86 (m, 1H, H13), 4.41 (dd, J=6.6,10.4 Hz, 1H, H7), 4.28 (d, J=8.2 Hz, 1H, H20α), 4.12 (d, J=8.2 Hz, 1H,H20β), 3.86 (d, J=7.14 Hz, 1H, H3), 2.51 (m, 1H, H6α), 2.26 (s, 3H,4Ac), 2.22-2.03 (m, 2H, H14α, H14β), 1.93 (s, 3H, Me18), 1.84 (m, 1H,H6β), 1.64 (s, 3H, Me19), 1.19 (s, 3H, Me17), 1.12 (s, 3H, Me16),1.02-0.93 (m, 18H, SiCH₂ CH₃), 0.69-0.56 (m, 12H, SiCH₂ CH₃), 0.17 (s,9H, SiCH₃).

EXAMPLE 2 PREPARATION OF TAXOL ANALOGS WITH VARIOUS SUBSTITUENTS AT C-2a.13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-acetyl-10-deacetylbaccatin (III). ##STR19##

13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III). To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-10-deacetyl baccatin (III)(0.1 g, 0.12 mmol) in THF (6.0 mL) at 0° C. was added dropwise 60 μL ofa 1.0 M solution of Red-Al in toluene. The resulting mixture was stirredat 0° C. for 1 h and 3.0 mL of saturated aqueous NaHCO₃ was added. Thesolution was filtered and the solid was rinsed with EtOAc. The filtratewas concentrated under reduced pressure and diluted with EtOAc (50.0mL). The organic layer was separated and washed with brine (5.0 mL). Thecombined organic layer was dried over anhydrous Na₂ SO₄, filtered, andconcentrated under reduced pressure to give a crude solid (0.14 g) .Flash chromatography with 30% EtOAc in hexane gave pure13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) (84.5 mg, 96.6%) m.p. 73°-74° C. [α ]²⁵ _(Na) -24.0° (c0.5, CHCl₃), ¹ H NMR (CDCl ₃, 300 MHz), δ5.11 (s, 1H, H10), 4.94 (dd,J=1.7, 9.3 Hz, 1H, H5), 4.87 (m, 1H, H13), 4.62 (d, J=9.3 Hz, 1H, H20α),4.54. (d, J=8.8 Hz, 1H, H20β), 4.35 (dd, J=6.6, 10.4 Hz, 1H, H7), 3.86(m, 1H, H2), 3.47 (d, J=6.6 Hz, 1H, H3), 2.51 (m, 1H, H6α), 2.14 (s, 3H,4Ac), 2.02-1.83 (m, 3H, H14α, H14β, H6B), 1.60 (s, 3H, Me18), 1.60 (s,3H, Me19), 1.14 (s, 3H, Me17), 1.07 (s, 3H, Me16), 0.99-0.92 (m, 18H,SiCH₂ CH₃), 0.66-0.55 (m, 12H, SiCH₂ CH₃), 0.13 (s, 9H, SiCH₃).##STR20##

13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) 1,2-carbonate. To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) (20.0 mg, 0.027 mmol) in CH₂ Cl₂ (4.0 mL) and pyridine(0.8 mL) at -78° C. was added 80 μL of a 3.4 M solution of COCl₂ inbenzene (10 eq). The mixture was warmed to -10° C. (ice-acetone) andkept for 30 min at -10° C. Saturated aqueous NaHCO₃ (5.0 mL ) was addedand the mixture were extracted with EtOAc (3×10 mL). The organic layerwas washed with aqueous 10% CuSO₄ until all pyridine disappeared thenbrine (5.0 mL ). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a crudesolid (22.5 mg). Plug filtration with 20% EtOAc in hexane gave pure13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) 12-carbonate(20.5mg, 99.0%) m.p. 144°-146° C. [α]²⁵ _(Na)-27.5° (c0.5, CHCl₃), 1H NMR (CDCl₃, 300 MHz), δ5.15 (s, 1H, H10), 4.90(m, 2H, H5, H13), 4.58 (d, J=8.9 Hz, 1H, H20α), 4.44 (d, J=8.6 Hz, 1H,H20β), 4.43 (d, J=5.4 Hz, 1H, H2), 4.37 (dd, J=6.6, 10.4 Hz, 1H, H7),3.43 (d, J=5.6 Hz, 1H, H3), 2.56 (m, 1H, H6α), 2.37 (m, 1H, 14α), 2.14(s, 3H, 2.13 (m, 1H, H14β), 1.92 (s, 3H, Me18), 1.84 (m, 1H, H6β), 1.64(s, 3H, Me19), 1.22 (s, 3H, Me17), 1.17 (s, 3H, Me16), 0.99-0.85 (m,18H, SiCH₂ CH₃), 0.66-0.55 (m, 12H, SiCH₂ CH₃), 0.17 (s, 9H, SiCH₃).##STR21##

13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-acetyl-10-deacetylbaccatin (III). To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) 1,2-carbonate (10.0mg, 0.014 mmol) in THF (0.5 mL) at 0°C. was added 40 μL of a 3.4 M solution (10 eq) of MeMgBr in ether. Thesolution was stirred for 1 h at 0° C. under N₂ and saturated aqueousNaHCO₃ was added (1.0 mL). The mixture was extracted with EtOAc (3×5.0mL) and the organic layer was washed with brine (5.0 mL), dried overanhydrous Na₂ SO₄, filtered and concentrated under reduced pressure togive a crude solid (11.3 mg). Flash chromatography with 20% EtOAc inhexane gave pure 13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2acetyl-10-deacetylbaccatin (III)(9.8 mg 95.9%) m.p. 201°-203° C. [α]²⁵ _(Na) -38.9° (c 0.5 CHCl₃) ¹ HNMR (CDCl₃, 300 MHz), δ5.34 (d, J=7.2 Hz, 1H, H2), 5.15 (s, 1H, H10),4.93 (dd, J=2.8, 9.3 Hz, 1H, H5), 4.83 (m, 1H, H13), 4.43 (d, J=7.7 Hz,1H, H20α), 4.38 (d, J=7.1 Hz, 1H, H20β), 4.18 (dd, J=6.1, 11.6 Hz, 1H,H7), 3.73 (d, J=6.6 Hz, 1H, H3), 2.54 (m, 1H, H6α, 2.20-2.03 (m, 2H,H14α, H14β), 2.15 (s, 3H, 4Ac), 2.07 (s, 3H, 2Ac), 1.96 (m, 1H, H6β),1.89 (s, 3H, Me18), 1.58 (s, 3H, Me19), 1.12 (s, 3H, Me17), 1.00 (s, 3H,Me16), 0.99-0.91 (m, 18H, SiCH₂ CH₃), 0.67-0.56 (m, 12H, SiCH₂ CH₃),0.16 (s, 9H, SiCH₃).

b. 13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10- deacetylbaccatin (III) ##STR22##

To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III ) 1,2-carbonate (10.0 mg, 0.014 mmol) in THF (0.5 mL) at-45° C. was added 78 μL of a 1.8 M solution of phenyllithium (10 eq) in30% ether/70% cyclohexane. The solution was stirred for 1 h at -45° C.under N₂ and saturated aqueous NaHCO was added (1.0 mL). The mixture wasextracted with EtOAc (3×5.0 mL). The organic layer was washed with brine(5.0 mL), dried over anhydrous Na₂ SO₄, filtered and concentrated underreduced pressure to give a crude solid (12.5 mg). Flash chromatographywith 10% EtOAc in hexane gave pure 13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetyl baccatin (III) (10.8mg, 94.5%).

c. 13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) ##STR23##

To a stirred solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (Ill) 1,2-carbonate (6.0 mg, 0.0082 mmol) in THF (0.5 mL) at 0°C. was added 60 μL of a 0.068 M solution (5 eq) of Red-Al in toluene.The resulting solution was stirred for 1 h at 0° C. under N₂, 1.0 mL ofsaturated aqueous NaHCO₃ was added, and the mixture was extracted withEtOAc (2×10.0 mL). The organic layer was washed with brine (5.0 mL),dried over anhydrous Na₂ SO₄, filtered and concentrated under reducedpressure to give a crude solid (6.75 mg). Flash chromatography with 30%EtOAc in hexane gave13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) (4.3 mg, 71.5%) and13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-formyl-10-deacetylbaccatin (Ill) (1.5 mg, 24.5%).

d.13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-p-fluorobenzoyl-10-deacetylbaccatin (III) ##STR24##

To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2--debenzoyl-10-deacetylbaccatin (III) (40.0 mg, 0.054 mmol) in THF (1.0 mL) at -78° C. under N₂was added dropwise 320 μL of a 0.328 M solution (2 eq) of LDA in THF.The mixture was stirred for 30 min at -78° C. and a solution of 26 μL (4eq) of p-fluorobenzoyl chloride in 100 μL of THF was added. After 1 hdiisopropylamine (100 μL) was added and the mixture was warmed to 25° C.After 10 min the mixture was diluted with aqueous NaHCO₃ (5.0 mL) andextracted with EtOAc (2×10.0 mL). The organic layer was washed withbrine (5.0 mL), dried over anhydrous Na₂ SO₄, filtered and concentratedunder reduced pressure to give a crude solid (67.5 mg). Flashchromatography with 10% EtOAc in hexane gave13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2debenzoyl-2-p-fluorobenzoyl-10-deacetylbaccatin (III) (36.9 mg, 80.2%) m.p. 216°-218° C. [α]²⁵ _(Na) - 45 6° (c0.5 CHCl₃) 1H NMR (CDCl₃, 300 MHz) δ8.10 (m, 2H, aromatic), 7.18-7.12(m, 2H, aromatic), 5.60 (d, J=7.2 Hz, 1H, H2), 5.19 (s, 1H, H10), 4.94(dd, J=1.7, 9.9 Hz, 1H, H5), 4.86 (m, 1H, H13), 4.41 (dd, J=6.9, 10.4Hz, 1H, H7), 4.26 (d, J=8.2 Hz, 1H, H20α), 4.11 (d, J=8.2 Hz, 1H, H20β),3.86 (d, J=6.6 Hz, 1H, H3), 2.51 (m, 1H, H6α), 2.25 (s, 3H, 4Ac), 2.11(m, 2H, H14α, H14β), 2.04 (s, 3H, Me18), 1.88 (m, 1H, H6β), 1.64 (s, 3H,Me19), 1.18 (s, 3H, Me17), 1.12 (s, 3H, Me16), 1.02-0.92 (m, 18H, SiCH₂CH₃), 0.69-0.54 (m, 12H, SiCH₂ CH₃), 0.17 (s, 9H, SiCH₃).

e. 7,10- Bis-O-triethylsilyl-2-debenzoyl-2-p-fluorobenzoyl-10-deacetylbaccatin (III) ##STR25##

To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-p-fluorobenzoyl-10-deacetylbaccatin (III) (30.0 mg, 0.035 mmol) in 2.25 mL of acetonitrile and 2.25mL of THF in a polyethylene vial was added dropwise 48 μL of pyridineand 75 μL of 48% aqueous HF. The reaction mixture was stirred at 25° C.for 12 h and then diluted with EtOAc (20.0 mL). Saturated aqueous NaHCO₃was added until gas evolution ceased. The organic layer was separated,washed with brine (3.0 mL), dried over anhydrous Na₂ SO₄, filtered andconcentrated under reduced pressure to give a crude solid (36.2 mg).Flash chromatography with 25% EtOAc in hexane gave7,10-bis-O-triethylsilyl-2-debenzoyl-2-p-fluorobenzoyl-10-deacetylbaccatin (III) (21.5 mg, 78.8%) and10-O-triethylsilyl-2-debenzoyl-2-p-fluorobenzoyl-10-deacetyl baccatin(III) (3.8 mg, 15.9% ). m.p. 186°-188° C., [α]²⁵ _(Na-) 48.2° (c 0.5CHCl₃) 1H NMR (CDCl₃, 300 MHz) δ8.11 (m 2H aromatic), 7.26-7.11 (m, 2H,aromatic), 5.59 (d, J=6.6 Hz, 1H, H2), 5.21 (s, 1H, H10), 4.94 (dd,J=1.7, 9.34 Hz, 1H, H5), 4.84 (m, 1H, H13), 4.42 (dd, J=6.6, 10.4 Hz,1H, H7), 4.26 (d, J=8.24 Hz, 1H, H20α), 4.14 (d, J =8.25 Hz, 1H, H20β),3.90 (d, J=6.6 Hz, 1H, H3), 2.54 (m, 1H, H6α), 2.26 (s, 3H, 4Ac), 2.05(m, 2H, H14α, H14β), 2.02 (s, 3H, Me18 ), 1.88 (m, 1H, H6β), 1.65 (s,3H, Me19), 1.18 (s, 3H, Me17), 1.05 (s, 3H, Me16), 1.02-0.92 (m, 18H,SiCH₂ CH₃), 0.69-0.53 (m, 12H, SiCH₂ CH₃).

f. 2-Debenzoyl-2-p-fluorobenzoyl taxol. ##STR26##

To a solution of7,10-bis-O-triethylsilyl-2-debenzoyl-2-p-fluorobenzoyl-10-deacetylbaccatin (III) (20.0 mg, 0.026 mmol) in 1.0 mL of THF at -45° C. wasadded dropwise 16 μL of a 1.64 M solution of n-butyllithium in hexane.After 0.5 h at -45° C., a solution of (±)cis-1-benzoyl-3-triethylsilyloxy-4-phenyl azetidin-2-one (50.0 mg, 0.13mmol) in THF (0.5 mL) was added dropwise to the mixture. The solutionwas warmed to 0° C. and kept at that temperature for 1 h and 1 mL of a10% solution of AcOH in THF was added. The mixture was partitionedbetween saturated aqueous NaHCO₃ and 60/40 ethyl acetate/hexane.Evaporation of the organic layer gave a residue which was purified byfiltration through silica gel with 20% EtOAc in hexane to give a crudesolid (32.5 mg). To a solution of this solid in 1.6 mL of acetonitrileand 79 μL of pyridine at 0° C. was added 240 μL of 48% aqueous HF. Themixture was stirred at 0° C. for 3 h, then at 25° C. for 13 h, andpartitioned between saturated aqueous sodium bicarbonate and ethylacetate. Evaporation of the ethyl acetate solution gave a crude solid(24.4 mg) which was purified by flash chromatography with 70% EtOAc inhexane to give 2-debenzoyl-2-p-fluorobenzoyl taxol (15.2 mg, 70.4%).m.p. 180°-183° C., [α]²⁵ _(Na-) 56 9° (c 0.5 CHCl₃) ¹ H NMR (CDCl₃, 300MHz) δ8.15 (m, 2H aromatic), 7.73 (m, 2H, aromatic), 7.52-7.34 (m, 8H,aromatic), 7.20 (m, 2H, aromatic), 7.07 (d, J=9.3 Hz, 1H, NH), 6.22 (dd,J=8.8, 8.8 Hz, 1H, H13), 5.79 (dd, J=8.8, 2.7 Hz, 1H, H3'), 5.64 (d,J=7.1 Hz, 1H, H2β), 5.17 (s, 1H, H10), 4.94 (dd, J=9.3, 1.7 Hz, 1H, H5),4.79 (m, 1H, H2'), 4.29-4.15 (m, 3H, H7, H20α, H20β), 3.90 (d, J=7.1 Hz,1H, H3), 3.56 J=5.0 Hz, 1H, 2'OH), 2.58 (m, 1H, H6α), 2.38 (s, 3H, 4Ac),2.28 (m, 2H, H14α, H14β), 1.82 (m, 1H, H6β), 1.79 (s, 3H, Me18), 1.74(s, 3H, Me19), 1.20 (s, 3H, Me17), 1.10 (s, 3H, Me16).

g.13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-(2-furoyl)-10-aleacetylbaccatin (III) ##STR27##

To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2--debenzoyl-10-deacetylbaccatin (III) (40.0 mg, 0.054 mmol) in THF (1.0 mL) at -78° C. under N₂was added dropwise 320 μL of a 0.328 M solution (2 eq) of LDA in THF.The mixture was stirred for 30 rain at -78° C. and a solution of 26 μL(4 eq) of p-fluorobenzoyl chloride in 100 μL of THF was added. After 1 hdiisopropylamine (100 μL) was added and the mixture was warmed to 25° C.After 10 rain the mixture was diluted with aqueous NaHCO₃ (5.0 mL ) andextracted with EtOAc (2×10.0 mL). The organic layer was washed withbrine (5.0 mL), dried over anhydrous Na₂ SO₄, filtered and concentratedunder reduced pressure to give a crude solid (64.2 mg). Flashchromatography with 15% EtOAc in hexane gave13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-(2-furoyl)-10-deacetylbaccatin (III) (33.9 mg 76.3%) m.p. 208°-210° C. [α]²⁵ _(Na-) 49.6° (c0.5 CHCl₃) 1H NMR (CDCl₃, 300 MHz) δ7.62 (m, 1H, furoyl), 7.20 (m, 1H,furoyl), 6.50 (m, 1H, furoyl), 5.52 (d, J=7.1 Hz, 1H, H2), 5.18 (s, 1H,H10), 4.95 (dd, J=1.6, 9.4 Hz, 1H, H5), 4.85 (m, 1H, H13), 4.41 (dd,J=6.9, 10.4 Hz, 1H, H7), 4.38 (d, J=8.8 Hz, 1H, H20α), 4.15 (d, J=8.2Hz, 1H, H20β), 3.82 (d, J =6.6Hz, 1H, H3), 2.51 (m, 1H, H6α), 2.22 (s,3H, 4Ac), 2.10 (m, 2H, H14α, H14β), 1.92 (s, 3H, Me18), 1.89 (m, 1H,H6β), 1.64 (s, 3H, Me19), 1.17 (s, 3H, Me17), 1.12 (s, 3H, Me16),1.01-0.93 (m, 18H, SiCH₂ CH₃), 0.69-0.52 (m, 12H, SiCH₂ CH₃), 0.16 (s,9H, SiCH₃).

h. 7,10-Bis-O-triethylsilyl-2-debenzoyl-2-(2-furoyl)-10-deacetylbaccatin (III) ##STR28##

To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-(2-furoyl)-10-deacetylbaccatin (III) (30.0 mg, 0.036 mmol) in 2.25 mL of acetonitrile and 2.25mL of THF in a polyethylene vial was added dropwise 48 μL of pyridineand 75 μL of 48% aqueous HF. The reaction mixture was stirred at 25 ° C.for 12 h and then diluted with EtOAc (20.0 mL). Saturated aqueous NaHCO₃was added until gas evolution ceased. The organic layer was separated,washed with brine (3.0 mL), dried over anhydrous Na₂ SO₄, filtered andconcentrated under reduced pressure to give a crude solid (33.4 mg).Flash chromatography with 30% EtOAc in hexanegave7,10-bis-O-triethylsilyl-2-debenzoyl-2-(2-furoyl)-10-deacetylbaccatin(III) (21.3 mg, 78.8%) and10-O-triethylsilyl-2-debenzoyl-2-(2-furoyl)-10-deacetyl baccatin (III)(4.9 mg 21.4%) m.p. 179°-181° C. [α ]²⁵ _(Na-) 45.6° (c 0.5, CHCl₃), ¹ HNMR (CDCl₃, 300 MHz) δ7.62 (m, 1H, furoyl), 7.21 (m, 1H, furoyl), 6.53(m, 1H, furoyl), 5.51 (d, J=7.1 Hz, 1H, H2), 5.20 (s, 1H, H10), 4.94(dd, J=1.7, 9.3 Hz, 1H, H2), 4..82 (m, 1H, H13), 4.43-4.37 (m, 2H, H7,H20α), 4.18 (d, J=8.2 Hz, 1H, H20β), 3.87 (d, J=7.2 Hz, 1H, H3), 2.52(m, 1H, H6α), 2.23 (s, 3H, 4Ac), 2.10 (m, 2H, H14α, H14β), 2.01 (s, 3H,Me18), 1.88 (m, 1H, H6β), 1.64 (s, 3H, Me19), 1.17 (s, 3H, Me17), 1.04(s, 3H, Me16), 1.02-0.92 (m, 18H, SiCH₂ CH₃), 0.69-0.54 (m, 12H, SiCH₂CH₃).

i. 2-Debenzoyl-2-(2-furoyl)taxol. ##STR29##

To a solution of7,10-bis-O-triethylsilyl-2-debenzoyl-2-(2-furoyl)-10-deacetyl baccatin(III) (20 mg, 0.027 mmol) in 1.0 mL of THF at -45° C. was added dropwise16 μL of a 1.64 M solution of n-butyllithium in hexane. After 0.5 h at-45° C., a solution of (+) cis-1-benzoyl-3-triethylsilyloxy-4-phenylazetidin-2-one (50.0 mg, 0.13 mmol) in THF (0.5 mL) was added dropwiseto the mixture. The solution was warmed to 0° C. and kept at thattemperature for 1 h and 1 mL of a 10% solution of AcOH in THF was added.The mixture was partitioned between saturated aqueous NaHCO₃ and 60/40ethyl acetate/hexane. Evaporation of the organic layer gave a residuewhich was purified by filtration through silica gel with 20% EtOAc inhexane to give a crude solid (31.7 mg). To a solution of this solid in1.6 mL of acetonitrile and 79 μL of pyridine at 0° C. was added 240 μLof 48% aqueous HF. The mixture was stirred at 0° C. for 3 h, then at 25°C. for 13 h, and partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate. Evaporation of the ethyl acetate solutiongave a crude solid (24.4 mg) which was purified by flash chromatographywith 70% EtOAc in hexane to give 2-debenzoyl-2-(2-furoyl) taxol (14.9 mg68.8%) m.p. 176°-179° C. [α]²⁵ _(Na-) 43.1° (c 0.5, CHCl₃), ¹ H NMR(CDCl₃, 300 MHz) δ7.76-7.32 (m, 12H, aromatic) 7.08 (d, J=8.8 Hz, 1H,NH), 6.60 (m, 1H, furoyl), 6.20 (dd, J=8.8, 8.8 Hz, 1H, H13), 5.78 (dd,J=8.8, 2.8 Hz, 1H, H3'), 5.56 (d, J=7.1 Hz, 1H, H2β), 5.16 (s, 1H, H10),4.93 (dd, J=9.3, 1.7 Hz, 1H, H5), 4.78 (m, 1H, H2'), 4.40 (d, J=8.3 Hz,1H, H20α), 4.24 (d, J= 8.2 Hz, 1H, 20β), 4.19 (m, 1H), H7), 3.86 (d,J=7.1 Hz, 1H, H3), 3.57 (d, J=5.0 Hz, 1H, 2'OH), 2.56 (m, H, H6α), 2.35(s, 3H, 4Ac), 2.24 (m, 2H, H14α, H14β), 1.83 (m, 1H, H6β), 1.76 (s, 3H,Me18), 1.73 (s, 3H, Me19), 1.19 (s, 3H, Me17), 1.08 (s, 3H, Me16).

EXAMPLE 3 PREPARATION OF TAXOL ANALOGS WITH VARIOUS SUBSTITUENTS AT C-4a.13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-4,10-bisdeacetylbaccatin(III). ##STR30##

To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-10-deacetyl baccatin (III)(0.1 g, 0.012 mmol) in ether (4.0 mL) at -10 ° C. was added dropwise 320μL of a 1.0 M solution of lithium aluminum hydride (LAH) in ether. Theresulting mixture was slowly warmed from -10 ° C. to 0 ° C. over a 2 hperiod and 3.0 mL of saturated aqueous NaHCO₃ was added. The solutionwas filtered and the solid was rinsed with EtOAc. The filtrate wasconcentrated under reduced pressure and diluted with EtOAc (50.0 mL).The organic layer was separated and washed with brine (5.0 mL). Thecombined organic layer was dried over anhydrous Na₂ SO₄, filtered, andconcentrated under reduced pressure to give a crude oil (0.15 g). Flashchromatography with 30% EtOAc in hexane gave pure13-O-trimethylsilyl-7,10-bis-O--triethylsilyl-2-debenzoyl-4,10-bisdeacetylbaccatin (III) (72.0 mg, 85.8% ) as a colorless oil. [α]²⁵ _(Na-) 25 5°(c 0.5, CHCl₃) ¹ H NMR (CDCl₃, 300 MHz), δ5.15 (s, 1H, H10), 4.73 (dd,J=1.8, 8.9Hz, 1H, H5), 4.65 (m, 1H, H13), 4.53 (d, J=9.3 Hz, 1H, H20α),4.39 (d, J=8.2 Hz, 1H, H20β), 4.00 (dd, J=6.0, 11.5 Hz, 1H, H7), 3.76(m, 1H, 2H), 3.44 (d, J=11.0 Hz, 2OH), 3.27 (d, J=6.0 Hz, 1H, H3), 2.45(m, 2H, H6α, H14β), 2.08-1.93 (m, 2H, H6β, H14β), 1.84 (s, 3H, Me18),1.53 (s, 3H, Me19), 1.09 (s, 3H, Me17), 1.05 (s, 3H, Me16), 1.01-0.91(m, 18H, SiCH₂ CH₃), 0.66-0.53 (m, 12H, SiCH₂ CH₃), 0.23 (s, 9H, SiCH₃).

b. 13 -O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) ##STR31##

To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-4,10-bisdeacetylbaccatin (III) (10.0 mg, 0.0143 mmol) in THF (1.0 mL) at -78 ° C. wasadded 440 μL of a 0.328 M solution (10 eq) of lithium diisopropyl amide(LDA) in THF under N₂. The solution was stirred for 30 rain at -78 ° C.and 200 μL of a 1.4 M solution of acetyl chloride in THF (20 eq) wasadded. The mixture were stirred for 1 h at -78 ° C., saturated aqueousNaHCO₃ (2.0 mL) was added, and the mixture was extracted with EtOAc(2×10 mL). The organic layer was washed with brine (5.0 mL), dried overanhydrous Na₂ SO₄, filtered and concentrated to give a crude oil (12.7mg). Flash chromatography from 25% EtOAc to 50% EtOAc in hexane gave13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) (6.1 mg, 57.6% ),13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-acetyl-4,10-bisdeacetylbaccatin (III) (1.89 mg, 17.9%), recovered13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-4,10-bisdeacetylbaccatin (III) (1.2 mg, 12.0%) and13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-acetyl-4,10-bisdeacetylbaccatin (III) (<1.0 mg).

c.13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-4,10-bisdeacetylbaccatin(III) 1,2-carbonate ##STR32##

To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-4,10-bisdeacetylbaccatin (III) (20.0 mg, 0.029mmol) in CH₂ Cl₂ (4.0 mL ) and pyridine(0.8 mL ) at -78° C. was added 80 μL of a 3.4 M solution of COCl₂ inbenzene (10 eq). The mixture was warmed to -10° C. (ice-acetone) andkept for 30 rain at -10 ° C. Saturated aqueous NaHCO₃ (5.0 mL) was addedand the mixture were extracted with EtOAc (3×10 mL). The organic layerwas washed with aqueous 10% CuSO₄ then brine (5.0 mL), dried overanhydrous Na₂ SO₄, filtered and concentrated under reduced pressure togive a crude solid (21.9 mg). Plug filtration with 20% EtOAc in hexanegave pure13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-4,10-bisdeacetylbaccatin (III) 1,2-carbonate (20.8 mg, 98.9%). m.p. 147°- 148 ° C. [α]²⁵_(Na-) 28.8° (c 0.5 CHCl₃) ¹ H NMR (CDCl₃, 300 MHz), δ5.21 (s, 1H, H10),4.76 (dd, J=2.8, 9.9 Hz, 1H, H5), 4.65 (m, 1H, H13), 4.54 (d, J=8.8 Hz,1H, H20α), 4.52 (d, J=8.3 Hz, 1H, H20β), 4.32 (d, J=5.0 Hz, 1H, H2),4.10 (dd, J=6.6, 11.0 Hz, 1H, H7), 3.10 (d, J=5.3 Hz, 1H, H3), 2.54 (m,3H, H6α, H14β, H14B), 1.99 (m, 1H, H6β), 1.92 (s, 3H, Me18), 1.61 (s,3H, Me19), 1.17 (s, 3H, Me17), 1.12 (s, 3H, Me16), 1.01-0.91 (m, 18H,SiCH₂ CH₃), 0.67-0.56 (m, 12H, SiCH₂ CH₃), 0.23 (s, 9H, SiCH₃).

d. 13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-acetyl-4,10-bisdeacetylbaccatin (III) ##STR33##

To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-4,10-bisdeacetylbaccatin (III) (10.0 mg, 0.014 mmol) in THF (0.5 mL) at 0 ° C. was added40 μL of a 3.4 M solution (10 eq) of MeMgBr in ether. The solution wasstirred for 1 h at 0 ° C. under N₂ and saturated aqueous NaHCO₃ wasadded (1.0 mL). The mixture was extracted with EtOAc (3×5.0 mL) and theorganic layer was washed with brine (5.0 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a crudesolid (11.9 mg). Flash chromatography with 20% EtOAc in hexane gave pure13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-2-acetyl-4,10-bisdeacetylbaccatin (III) (9.9 mg, 97.0%). m.p. 198°-201° C., [α]²⁵ _(Na-) 39.9° (c0.5 CHCl₃) ¹ H NMR (CDCl₃ , 300 MHz) δ5.27 (d J=5.5 Hz, 1H, H2), 5.22(s, 1H, H10), 4.71 (m, 1H, H13), 4.58 (dd, J=2.8, 9.3 Hz, 1H, H5), 4.41(d, J=7.7 Hz, 1H, H20α), 4.35 (d, J=7.1 Hz, 1H, H20β), 4.01 (dd, J=6.1,11.6 Hz, 1H, H7), 3.74 (s, 1H, 4OH), 3.47 (d, J =5.5 Hz, 1H, H3), 2.45(m, 1H, H6α, 2.24-2.04 (m, 2H, H14αH14β), 2.06 (s, 3H, 2Ac), 1.96 (m,1H, H6β), 1.88 (s, 3H, Me18), 1.46 (s, 3H, Me19), 1.14 (s, 3H, Me17),1.02 (s, 3H, Me16), 0.99-0.91 (m, 18H, SiCH₂ CH₃), 0.67-0.56 (m, 12H,SiCH₂ CH₃), 0.24 (s, 9H, SiCH₃).

e. 13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-4,10-bisdeacetylbaccatin (III) ##STR34##

To a solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-4,10-bisdeacetylbaccatin (III) 1,2-carbonate (10.0 mg, 0.014 mmol) in THF (0.5 mL) at-45 ° C. was added 78 μL of a 1.8 M solution of phenyllithium (10 eq) in30% ether/70% cyclohexane. The solution was stirred for 1 h at -45 ° C.under N₂ and saturated aqueous NaHCO was added (1.0 mL). The mixture wasextracted with EtOAc (3×5.0 mL). The organic layer was washed with brine(5.0 mL), dried over anhydrous Na₂ SO₄, filtered and concentrated underreduced pressure to give a crude solid (12.8 mg). Flash chromatographywith 50% EtOAc in hexane gave pure13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-4,10-bisdeacetyl baccatin(III) (9.9 mg, 98.5%). m.p 177°-179 ° C. [α]²⁵ _(Na-) 44.5° (c 0.3CHCl₃) 1H NMR (CDCl₃, 300 MHz) δ8.05 (d, J=7.2 Hz, 2H, benzoate ortho),7.60-7.37 (m, 3H, aromatic), 5.61 (d, J=6.1 Hz, 1H, H2), 5.25 (s, 1H,H10), 4.74 (m, 1H, H13), 4.57 (dd, J =1.7, 9.3 Hz, 1H, H5), 4.38 (d,J=8.2 Hz, 1H, H20α), 4.12 (d, J=8.2 Hz, 1H, H20b), 4.05 (dd, J=6.1, 12.1Hz, 1H, H7), 3.69 (d, J=6.0 Hz, 1H, H3), 2.55 (m, 1H, H6α), 2.42 (m, 2H,H14α, H14β), 2.04 (s, 3H, Me18), 1.99 (m, 1H, H6β), 1.64 (s, 3 H, Me19),1.20 (s, 3H, Me17), 1.04 (s, 3H, Me16), 1.01-0.90 (m, 18H, SiCH₂ CH₃),0.70-0.56 (m, 12H, SiCH₂ CH₃).

f. 13-O-Trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) 1,2-carbonate ##STR35##

To a stirred solution of13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-4,10-bisdeacetylbaccatin (III ) 1,2-carbonate (8.0 mg, 0.011 mmol) in pyridine (0.5 mL)was added Ac₂ O (100 μL) and DMAP (50 mg). The solution was heated atreflux under N₂ for 12 h, cooled to room temperature, and 15.0 mL ofEtOAc was added. The organic layer was washed with 10% aqueous CuSO₄ andbrine (5.0 mL), dried over anhydrous Na₂ SO₄, filtered and concentratedunder reduced pressure to give a crude solid (22.0 mg). Flashchromatography with 20% EtOAc in hexane gave13-O-trimethylsilyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetylbaccatin (III) 1,2-carbonate (4.4 mg, 53.0% ) and13-O-acetyl-7,10-bis-O-triethylsilyl-2-debenzoyl-10-deacetyl baccatin(III) 1,2-carbonate (2.3 mg, 27.8%).

EXAMPLE 4 10-Desacetoxy baccatin III:

To a solution of baccatin III (20 mg; 0.034 mmol) in THF (0.09 mL) at 0°C. under nitrogen was added a solution of SmI₂ (0.1 M; 0.9 mL; 0.09mmol) in THF. After stirring 45 minutes at 0° C. the flask was opened tothe air, and the reaction mixture diluted with ethyl acetate (10 mL).The mixture was poured into aqueous HCl (0.2N; 25 mL), extracted withethyl acetate, and the extract was washed successively with saturatedaqueous NaHCO₃ and brine, dried over Na₂ SO₄ and evaporated. The productwas isolated by flash chromatography (SiO₂ ; 80% ethyl acetate-hexanes)affording 16.6 mg (92%) of 10-desacetoxybaccatin III which wasrecrystallized from CHCl₃ -hexanes, mp 230°-232 ° C. [α]²⁵ _(Na-) 103.6(c=0.00195 CHCl₃) IR (cm⁻¹): 3100 2970, 2950, 2900, 1750, 1710, 1460,1370, 1320, 1270, 1255, 1110, 980, 890, 760, 700. ¹ H-nmr (500 MHz,CDCl₃) δ8.11 (dd; 2H; J=8.4, 1.2 Hz; o-Bz); 7.61 (dt; 1H; J=7.5,1.2 Hz;p-Bz); 7.48 (br t; 2H; J=7.8 Hz; m-Bz); 5.66 (br d; 1H; J=6.9 Hz; H-2β);4.98 (br dd; 1H; J=9.4,2; H-5a); 4.83 (br; 1H; w1/219 Hz; H-13β); 4.34(dt; 1H; J= 11.2, 7.8Hz; H-7α); 4.31 (br d; 1H;J=8.4 Hz; H-20α); 4.17(br d; 1H; J=6.9Hz; H-3α); 4.15 (dd; 1H; J=8.4, 1Hz; H-20β); 3.84 (d;1H; J=15.6 Hz; H-10α); 3.46 (ddd; 1H; J=15.6,3.7,1.6 Hz; H-10β); 2.64(ddd; 1H; J=14.4,9.4,6.9 Hz; H-6α); 2.29 (s; 3H; 4-OAc); 2.28 (m; 2H;H-14α and H-14β); 1.95 (t; 3H; J=1.6 Hz; 18-Me); 1.94 (d, 1H; J=6.8 Hz;13-OH); 1.79 (ddd; 1H; J=14.4, 11.2, 2.1 Hz; H-6β); 1.64 (s; 3H; 19-Me);1.58 (s; 1H; 1-OH); 1.38 (d; 1H; J=7.8 Hz; 7-OH); 1.13 (s, 3H; 16-Me);1.06 (s, 3H; 17-Me).

EXAMPLE 5 7-Triethylsilyl-10-desacetoxy baccatin III:

To a stirred solution of 10-desacetoxybaccatin III (10.0 mg; 0. 019mmol) in anhydrous pyridine (0.05 mL) at room temperature and undernitrogen, triethylchlorosilane (15 L; 0.09 mmol) was added and theresulting mixture was stirred at room temperature for 48 h. Afterdiluting with ethyl acetate (5 mL) the mixture was poured into saturatedaqueous NaHCO₃ (25 mL) and extracted with ethyl acetate. The extract waswashed successively with water, 10% aqueous CuSO₄ and brine, dried overNa₂ SO₄ and evaporated. The product was purified by flash chromatography(SiO₂ ; 40% EA-hexanes) affording 11.1 mg (91%) of7-triethylsilyl-10-desacetoxybaccatin III.

EXAMPLE 6 10-Desacetoxytaxol:

To a stirred solution of taxol (35 mg; 0.041 mmol) in THF (0.1 mL) at 0°C. under nitrogen was added a solution of SmI₂ (0.1 M; 1.0 mL; 0.10mmol) in THF. After stirring 45 minutes at 0 ° C. the flask was openedto the air and the reaction mixture diluted with ethyl acetate (10 mL).The mixture was poured into aqueous HCl (0.2N; 25 mL), extracted withethyl acetate, and the extract was washed successively with saturatedaqueous NaHCO₃ and brine, dried over Na₂ SO₄ and evaporated. The productwas isolated by flash chromatography (SiO₂ ; 80% ethyl acetate-hexanes)affording 29.4 mg (90%) of 10-desacetoxytaxol.

What we claim is:
 1. A process for the preparation of a derivative oranalog of baccatin III or 10-desacetyl baccatin III from a derivative oranalog of baccatin III or 10-desacetyl baccatin III which comprises a C2benzoate and/or a C4 acetate substituent, the process comprisingselectively reducing the C2 benzoate substituent and/or the C4 acetatesubstituent with an aluminate to the corresponding hydroxy group(s) andacylatingthe C2 hydroxy substituent and/or the C4 hydroxy substituent toconvert the C2 hydroxy substituent to R₇ COO-- and/or convert the C4hydroxy substituent to R₈ COO-- wherein R₇ and R₈ are independently H,C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, monocyclic aryl, ormonocyclic heteroaryl.
 2. The process of claim 1 wherein the derivativeor analog of baccatin III or 10-desacetyl derivative has the formula##STR36## wherein R₁ is H, --OH, protected hydroxy, or --OCOR₆,R₂ is Hor a hydroxy protecting group, or ##STR37## R₃ is H or R₇ CO--, R₄ is Hor R₈ CO--, R₅ is --OH or protected hydroxy, R₆, R₇, and R₈ areindependently H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, moncyclicaryl, or monocyclic heteroaryl; R₉ is --OR₁₄, --SR₁₅, or --NR₁₆ R₁₇ ;R₁₀ is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₁₁ andR₁₂ are independently hydrogen, alkyl, or alkenyl, alkynyl, aryl, acylor heteroaryl, provided R₁₁ and R₁₂ are not both acyl; R₁₃ is --COR₁₈,--COOR₁₈, --COSR₁₈, --CONR₁₂ R₁₈, or --SO₂ R₁₉, R₁₄ is hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group, R₁₅ isalkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protectinggroup, R₁₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;R₁₇ is an amino protecting group; R₁₈ is alkyl, alkenyl, alkynyl, aryl,or heteroaryl, and R₁₉ is alkyl, alkenyl, alkynyl, aryl, heteroaryl,--OR₁₅, or --NR₁₂ R₁₆.
 3. The process of claim 1 wherein the C2 benzoatesubstituent and/or the C4 acetate substituent of the derivative ofbaccatin III or 10-desacetyl baccatin III are selectively reduced withlithium aluminum hydride or sodium bis(2-methoxyethoxy) aluminumhydride.
 4. The process of claim 1 wherein R₇ is p-fluoro-phenyl.
 5. Theprocess of claim 2 wherein the C2 benzoate substituent and/or the C4acetate substituent of the derivative of baccatin III or 10-desacetylbaccatin III are selectively reduced with lithium aluminum hydride orsodium bis(2methoxyethoxy) aluminum hydride.
 6. The process of claim 1wherein R₇ is monocyclic aryl.
 7. The process of claim 1 wherein R₇ isC₁ -C₆ alkyl, C₁ -C₆ alkanoxy or halogen substituted monocyclic aryl. 8.The process of claim 1 wherein the derivative or analog of baccatin IIIor 10-desacetyl baccatin III is prepared from a C1 hydroxy C2 benzoatederivative of baccatin III or 10-desacetyl baccatin III, the C1 hydroxyC2 benzoate derivative is reduced with sodium bis(2-methoxyethoxy)aluminum hydride to form a 1,2-diol derivative, the 1,2-diol is reactedwith Cl₂ CO to form a 1,2-carbonate, and the 1,2-carbonate is reactedwith a nucleophilic reagent to convert the C2 substituent to R₇ COO--wherein R₇ is as defined in claim
 1. 9. A process for the preparation ofa derivative or analog of baccatin III or 10-desacetyl baccatin III froma derivative or analog of baccatin III or 10-desacetyl baccatin IIIwhich comprises a C2 benzoate and/or a C4 acetate group, the processcomprising selectively reducing the C2 benzoate substituent and/or theC4 acetate substituent of a derivative of baccatin III or 10-desacetylbaccatin III with lithium aluminum hydride or sodiumbis(2-methoxyethoxy) aluminum hydride to the corresponding hydroxygroup(s) and reacting the corresponding hydroxy group(s) with anacylating agent to convert the C2 hydroxy substituent to R₇ COO-- and/orconvert the C4 hydroxy substituent to R₈ COO-- wherein R₇ and R₈ areindependently H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, moncyclicaryl, or monocyclic heteroaryl.
 10. The process of claim 9 wherein theacylating agent is anhydride or an acid chloride.
 11. The process ofclaim 9 wherein R₇ is C₁ -C₆ alkyl, C₁ -C₆ alkanoxy or halogensubstituted monocyclic aryl.
 12. A process for the preparation of aderivative or analog of baccatin III or 10-desacetyl baccatin III from a1,2 carbonate derivative of baccatin III or 10-desacetyl baccatin III,the process comprising reacting the 1,2 carbonate with a nucleophilicreagent to convert the C2 substituent to R₇ COO-- wherein R₇ is H, C₁-C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, moncyclic aryl, or monocyclicheteroaryl and the 1,2 carbonate is a compound having the formula##STR38## wherein R₁ is H, --OH, protected hydroxy, or --OCOR₆,R₂ is Hor a hydroxy protecting group, or ##STR39## R₄ is H or R₈ CO--, R₅ isprotected hydroxy, R₆ is H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, moncyclic aryl, or monocyclic heteroaryl; R₈ is H, C₁ -C₆alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, moncyclic aryl, or monocyclicheteroaryl; R₉ is --OR₁₄, --SR₁₅, or --NR₁₆ R₁₇ ; R₁₀ is hydrogen,alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₁₁ and R₁₂ areindependently hydrogen, alkyl, or alkenyl, alkynyl, aryl, acyl orheteroaryl, provided R₁₁ and R₁₂ are not both acyl; R₁₃ is --COR₁₈,--COOR₁₈, --COSR₁₈, --CONR₁₂ R₁₈, or --SO₂ R₁₉, R₁₄ is hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group, R₁₅ isalkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protectinggroup, R₁₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;R₁₇ is an amino protecting group; R₁₈ is alkyl, alkenyl, alkynyl, aryl,or heteroaryl, and R₁₉ is alkyl, alkenyl, alkynyl, aryl, heteroaryl,--OR₁₅, or --NR₁₂ R₁₆.
 13. The process of claim 12 wherein thenucleophilic reagent is a Grignard reagent or an alkyllithium reagent.